Vagal tone, pain sensitivity and exercise-induced hypoalgesia: The effect of physical activity level.

BACKGROUND: Vagal activity has analgesic effects that are attributed to exercise-induced hypoalgesia (EIH). High vagal tone and low pain sensitivity are reported in individuals who routinely exercise yet, their association is unclear. Furthermore, it is unknown if the heightened vagal tone following high physical activity predicts and intensifies EIH. METHODS: Fifty-one healthy participants (27 low-moderately physically active; 27 females) underwent a resting-state electrocardiogram followed by heart rate variability analysis. Pain measurements, including pressure (PPT) and heat (HPT) pain thresholds, ratings of tonic heat pain (THP) and conditioned pain modulation (CPM) paradigm, were conducted pre- and post-exercise on a cycle ergometer. RESULTS: The highly active group demonstrated higher vagal tone compared to the low-moderately active (root mean square of successive differences between R-R intervals: 63.96.92 vs. 34.78 ms, p = 0.018; percentage of successive R-R intervals that exceed 50 ms: 24.41 vs. 11.52%, p = 0.012). Based on repeated-measure ANOVA, the highly active group showed higher PPT at pre-exercise, compared to the low-moderately active group (382 kPa vs. 327 kPa; p = 0.007). Post-exercise, both groups demonstrated EIH, increased HPT (p = 0.013) and decreased THP ratings (p < 0.001). Linear regression revealed that only in the low-moderately active group, higher vagal tone was associated with more efficient pre-exercise CPM and a greater reduction in THP ratings post-exercise (p ≤ 0.01). CONCLUSIONS: Highly active individuals demonstrate greater vagal tone and lower pain sensitivity but no greater EIH. Vagal tone moderates pain inhibition efficiency and EIH only in low-moderately active individuals. These findings suggest that physical activity level moderates the vagal-pain association via the endogenous analgesia system. SIGNIFICANCE: Highly physically active individuals exhibit greater vagal tone and reduced sensitivity to experimental pain, yet they do not benefit more from exercise-induced hypoalgesia (EIH) compared to low-moderately active individuals. Moreover, low-moderately active individuals with greater vagal tone exhibited more efficient endogenous pain inhibition and greater EIH, suggestive of the moderation effect of physical activity level on vagal-pain associations.

Implementation of pooled saliva tests for universal screening of cCMV infection.

Congenital cytomegalovirus (cCMV) is the most common intrauterine infection, leading to neurodevelopmental disabilities. Universal newborn infant screening of cCMV has been increasingly advocated. In the absence of a high-throughput screening test, which can identify all infected newborn infants, the development of an accurate and efficient testing strategy has remained an ongoing challenge. Here we assessed the implementation of pooled saliva polymerase chain reaction (PCR) tests for universal screening of cCMV, in two hospitals of Jerusalem from April 2022 through April 2023. During the 13-month study period, 15,805 infants (93.6% of all live newborn infants) were screened for cCMV using the pooled approach that has since become our routine screening method. The empirical efficiency of the pooling was six (number of tested newborn infants per test), thereby sparing 83% of the saliva tests. Only a minor 3.05 PCR cycle loss of sensitivity was observed for the pooled testing, in accordance with the theoretical prediction for an eight-sample pool. cCMV was identified in 54 newborn infants, with a birth prevalence of 3.4 per 1,000; 55.6% of infants identified with cCMV were asymptomatic at birth and would not have been otherwise targeted for screening. The study demonstrates the wide feasibility and benefits of pooled saliva testing as an efficient, cost-sparing and sensitive approach for universal screening of cCMV.

Quantitative Dynamic Allodynograph-A Standardized Measure for Testing Dynamic Mechanical Allodynia in Chronic Limb Pain.

BACKGROUND: Dynamic mechanical allodynia (DMA) is both a symptom and a central sensitization sign, yet no standardized method for quantifying the DMA area has been reported. This study aimed to establish psychometric properties for Quantitative Dynamic Allodynography (QDA), a newly developed protocol measuring the DMA area as a percentage of the body surface. METHODS: Seventy-eight patients aged 18-65 diagnosed with chronic complex regional pain syndrome (CRPS) participated in this study. Test-retest reliability was conducted twice, one week apart (N = 20), and inter-rater (N = 3) reliability was conducted on 10 participants. Disease severity (CRPS Severity Score, CSS), pain intensity (VAS), and quality of life (SF-36) measures were utilized to test construct validity. RESULTS: High inter-rater reliability (intraclass correlation coefficient (ICC) = 0.96, p < 0.001) and test-retest reliability (r = 0.98, p < 0.001) were found. Furthermore, the QDA score was found to be correlated with the CSS (r = 0.47, p < 0.001), VAS (r = 0.37, p < 0.001), and the SF-36 physical health total (r = -0.47, p < 0.001) scores. CONCLUSION: The QDA is the first developed reliable and valid protocol for measuring DMA in a clinical setting and may be used as a diagnostic and prognostic measure in clinics and in research, advancing the pain precision medicine approach.

"Feeling Unwanted, When Nobody Wants You Around": Perceptions of Social Pain Among People With Autism.

IMPORTANCE: A paucity of studies have focused on pain experiences among people with autism spectrum disorder, particularly those addressing social pain in daily life contexts or learning from the perspective of autistic people. OBJECTIVE: To explore the social pain experience of autistic people. DESIGN: A descriptive qualitative design followed by deductive thematic analysis. Interviews were semistructured to capture the social pain experience, coping strategies, and implications for the participation of autistic people. SETTING: Online interviews using Zoom videoconferencing software. PARTICIPANTS: Fifteen autistic people were recruited for the study using purposeful and criterion sampling. RESULTS: Four primary themes emerged from the data analysis: (1) a definition of social pain and the distinction between social pain and other types of pain; (2) the sources-internal, external, and combined-of social pain; (3) the loneliness outcome, which echoes the gap between the desire for and lack of social contacts; and (4) coping strategies pertaining to the continuum between inward and outward coping strategies to deal with social pain. CONCLUSION AND RELEVANCE: The study indicates the existence of a discrepancy between autistic people's need for social interactions and the social pain they experience. It calls for intervention programs for autistic people to improve their coping strategies and promote their self-acceptance and better inclusion in the community. What This Article Adds: Promoting social functioning is a prime role of occupational therapists, and this article adds a novel theoretical model that contributes to that role. The model represents the social pain experiences of autistic people and their strategies to overcome this phenomenon. Firsthand accounts of autistic people regarding social pain enable a better understanding of their desire to be involved in the social context. This study suggests directions for further intervention programs to assist autistic people in fulfilling their wish for social relationships and enabling their enhanced integration into society. Positionality Statement: We recognize that use of person-first versus identity-first language is a source of debate and controversy. We have chosen to use identity-first language for two reasons. First, studies indicate person with autism is the term least preferred by autistic people (Botha et al., 2021). Second, autistic is the term used by the majority of our participants during interviews.

Time since onset might be of essence: A recommendation to assess the effects of combination of non-pharmacological neuromodulatory approaches at early stage since symptoms onset.

In the past decade researchers began to assess the potential beneficial effects of non-invasive brain stimulation (NIBS) combined with a behavioral task as a treatment approach for various medical conditions. Transcranial direct current stimulation (tDCS) applied to the motor cortex combined with another treatment approach has been assessed as analgesic treatment in neuropathic and non-neuropathic pain conditions, and was found to exert only modest pain relief. Our group results show that combined tDCS and mirror therapy dramatically reduced acute phantom limb pain intensity with long-lasting effects, potentially preventing pain chronification. A review of the scientific literature indicates that our approach differs from that of others: We applied the intervention at the acute stage of the disease, whereas other studies applied the intervention in patients whose disease had already been established. We suggest that the timing of administration of the combined intervention is critical. Unlike in patients with chronic painful condition, in which the maladaptive plasticity associated with pain chronification and chronicity is well-consolidated, early treatment at the acute pain stage may be more successful in counterbalancing the not-yet consolidated maladaptive plasticity. We encourage the research community to test our hypothesis, both in the treatment of pain, and beyond.

Indifference or hypersensitivity? Solving the riddle of the pain profile in individuals with autism.

ABSTRACT: Excitatory-inhibitory (E/I) imbalance is a mechanism that underlies autism spectrum disorder, but it is not systematically tested for pain processing. We hypothesized that the pain modulation profile (PMP) in autistic individuals is characterized by less efficient inhibitory processes together with a facilitative state, indicative of a pronociceptive PMP. Fifty-two adults diagnosed with autism and 52 healthy subjects, age matched and sex matched, underwent quantitative sensory testing to assess the function of the (1) pain facilitatory responses to phasic, repetitive, and tonic heat pain stimuli and (2) pain inhibitory processes of habituation and conditioned pain modulation. Anxiety, pain catastrophizing, sensory, and pain sensitivity were self-reported. The autistic group reported significantly higher pain ratings of suprathreshold single ( P = 0.001), repetitive (46°C- P = 0.018; 49°C- P = 0.003; 52°C- P < 0.001), and tonic ( P = 0.013) heat stimuli that were cross correlated ( r = 0.48-0.83; P < 0.001) and associated with sensitivity to daily life pain situations ( r = 0.39-0.45; P < 0.005) but not with psychological distress levels. Hypersensitivity to experimental pain was attributed to greater autism severity and sensory hypersensitivity to daily stimuli. Subjects with autism efficiently inhibited phasic but not tonic heat stimuli during conditioned pain modulation. In conclusion, in line with the E/I imbalance mechanism, autism is associated with a pronociceptive PMP expressed by hypersensitivity to daily stimuli and experimental pain and less-efficient inhibition of tonic pain. The latter is an experimental pain model resembling clinical pain. These results challenge the widely held belief that individuals with autism are indifferent to pain and should raise caregivers' awareness of pain sensitivity in autism.

Resting-state functional connectivity predicts motor cortex stimulation-dependent pain relief in fibromyalgia syndrome patients.

MRI-based resting-state functional connectivity (rsFC) has been shown to predict response to pharmacological and non-pharmacological treatments for chronic pain, but not yet for motor cortex transcranial magnetic stimulation (M1-rTMS). Twenty-seven fibromyalgia syndrome (FMS) patients participated in this double-blind, crossover, and sham-controlled study. Ten daily treatments of 10 Hz M1-rTMS were given over 2 weeks. Before treatment series, patients underwent resting-state fMRI and clinical pain evaluation. Significant pain reduction occurred following active, but not sham, M1-rTMS. The following rsFC patterns predicted reductions in clinical pain intensity after the active treatment: weaker rsFC of the default-mode network with the middle frontal gyrus (r = 0.76, p < 0.001), the executive control network with the rostro-medial prefrontal cortex (r = 0.80, p < 0.001), the thalamus with the middle frontal gyrus (r = 0.82, p < 0.001), and the pregenual anterior cingulate cortex with the inferior parietal lobule (r = 0.79, p < 0.001); and stronger rsFC of the anterior insula with the angular gyrus (r = - 0.81, p < 0.001). The above regions process the attentional and emotional aspects of pain intensity; serve as components of the resting-state networks; are modulated by rTMS; and are altered in FMS. Therefore, we suggest that in FMS, the weaker pre-existing interplay between pain-related brain regions and networks, the larger the pain relief resulting from M1-rTMS.

Opening a window into the riddle of misophonia, sensory over-responsiveness, and pain.

Introduction: Misophonia and sensory over-responsiveness (SOR) share physiological and psychological symptoms. While individuals with SOR demonstrate pain perception alterations, these were not explored in misophonia. Methods: This exploratory study comprised thirty healthy adults with (n = 15; based on the Misophonia Questionnaire) and without misophonia. The Sensory Responsiveness Questionnaire (SRQ) was used for evaluating sensory responsiveness. In addition, psychophysical tests were applied for quantification of: (i) stimulus-response function of painful stimuli, (ii) the individual perceived pain intensity, (iii) pain modulation efficiency, (iv) auditory intensity discrimination capability, and (v) painful and unpleasantness responses to six ecological daily sounds using the Battery of Aversiveness to Sounds (BAS). Results: Individuals with misophonia reported higher scores in the SRQ-Aversive (p = 0.022) and SRQ-Hedonic (p = 0.029) scales as well as in auditory (p = 0.042) and smell (p = 0.006) sub-scales, indicating higher sensory responsiveness. Yet they were not identified with the SOR type of sensory modulation dysfunction. Groups did not differ in the pain psychophysical tests, and in auditory discrimination test scores (p > 0.05). However, in the misophonia group the BAS evoked higher pain intensity (p = 0.046) and unpleasantness (p <0.001) ratings in the apple biting sound, and higher unpleasantness rating in the scraping a dish sound (p = 0.007), compared to the comparison group. Conclusion: Findings indicate increased sensory responsiveness in individuals with misophonia, yet not defined as SOR. Thus, this suggests that misophonia and SOR are two distinct conditions, differing in their behavioral responses to painful and non-painful stimuli.

"When I'm in Pain, Everything Is Overwhelming": Implications of Pain in Adults With Autism on Their Daily Living and Participation.

Pain sensation in autism spectrum disorder (ASD) has been a growing research field in the last two decades. Existing pain research has focused on pain sensitivity, suggesting either hyposensitivity or hypersensitivity to pain in individuals with ASD. However, research about other aspects of pain experience is scarce. Moreover, most pain-related research in ASD focused on quantitative measures, such as neuroimaging or parental reports. Instead, this paper aimed to illuminate the various aspects of pain experience as perceived by adults with ASD. Its descriptive qualitative research design incorporated semi-structured interviews and deductive thematic analysis. This phenomenological approach captured the subjective pain experience through the lens of people with ASD. Four primary themes emerged from the data: (a) physical pain experience, including the sequence of pain sensitivity, pain awareness, pain-related emotional aspects, and pain communication; (b) direct and indirect coping strategies; (c) function and participation outcomes; and (d) suggestions for Healthcare Providers. The findings echo the crucial role of pain awareness and communication in the pain experience of people with ASD. These two factors have been reported as profoundly influencing coping strategies, function, and participation. The results emphasize the need to expand the exploration of pain in this population, calling for greater understanding, and listening to this population's unique pain profiles and experiences to promote better-suited evaluation, diagnosis, and intervention in pain conditions.

Susceptibility to movement-evoked pain following resistance exercise.

OBJECTIVE: To investigate the: (1) role of basic muscle pain sensitivity and psychological factors in the prediction of movement-evoked pain (MEP) following delayed onset muscle soreness (DOMS), and (2) association of MEP with changes in systemic muscle pain sensitivity following DOMS induction. METHODS: Fifty-one participants were assigned to either eccentric resistance exercise or control groups. They completed questionnaires evaluating psychological distress and underwent muscle pain sensitivity evaluation by the pressure pain threshold (PPT) test at the exercised and remote muscles, before and 24 hours following the intervention. MEP intensity was determined in response to lifting a 3kg canister using a visual analogue scale (VAS). RESULTS: The exercise group demonstrated MEP intensity of 5/10 on VAS and reduced PPTs at the main exercised muscle (p<0.001). A regression tree analyses revealed that the level of anxiety trait predicted a higher MEP intensity. A secondary analysis showed that 53% participants who were DOMS responders (MEP > mild intensity; ≥ 3/10 VAS) exhibited decreased PPTs in the exercised (p<0.001) and remote (p = 0.027) muscles following eccentric exercise. Characterization of DOMS responders revealed that, at baseline, they had lower PPTs in the exercised (p = 0.004) and remote (p = 0.001) muscles and reported higher psychological distress i.e., anxiety trait and depression symptoms (p<0.05), compared to non-responders. A regression analysis revealed that lower PPT or high levels of anxiety trait increased the probability to become a responder (p = 0.001). CONCLUSIONS: Susceptibility to MEP following DOMS is determined by muscle pain hypersensitivity and high levels of anxiety trait. MEP at the early stage of DOMS is linked with an increase in systemic muscle pain sensitivity suggestive of central mechanisms. This knowledge is valuable in translating science into clinical musculoskeletal pain management.

Clinical Effects of Repetitive Transcranial Magnetic Stimulation of the Motor Cortex Are Associated With Changes in Resting-State Functional Connectivity in Patients With Fibromyalgia Syndrome.

In this double-blinded, sham-controlled, counterbalanced, and crossover study, we investigated the potential neuroplasticity underlying pain relief and daily function improvements following repetitive transcranial magnetic stimulation of the motor cortex (M1-rTMS) in fibromyalgia syndrome (FMS) patients. Specifically, we used magnetic resonance imaging (MRI) to examine changes in brain structural and resting-state functional connectivity (rsFC) that correlated with improvements in FMS symptomology following M1-rTMS. Twenty-seven women with FMS underwent real and sham treatment series, each consisting of 10 daily treatments of 10Hz M1-rTMS over 2 weeks, with a washout period in between. Before and after each series, participants underwent anatomical and resting-state functional MRI scans and questionnaire assessments of FMS-related clinical pain and functional and psychological burdens. The expected reductions in FMS-related symptomology following M1-rTMS occurred with the real treatment only and correlated with rsFC changes in brain areas associated with pain processing and modulation. Specifically, between the ventromedial prefrontal cortex and the M1 (t = -5.54, corrected P = .002), the amygdala and the posterior insula (t = 5.81, corrected P = .044), and the anterior and posterior insula (t = 6.01, corrected P = .029). Neither treatment significantly changed brain structure. Therefore, we provide the first evidence of an association between the acute clinical effects of M1-rTMS in FMS and functional alterations of brain areas that have a significant role in the experience of chronic pain. Structural changes could potentially occur over a more extended treatment period. PERSPECTIVE: We show that the neurophysiological mechanism of the improvement in fibromyalgia symptoms following active, but not sham, rTMS applied to M1 involves changes in resting-state functional connectivity in sensory, affective and cognitive pain processing brain areas, thus substantiating the essence of fibromyalgia syndrome as a treatable brain-based disorder.

Central Sensitization and Psychological State Distinguishing Complex Regional Pain Syndrome from Other Chronic Limb Pain Conditions: A Cluster Analysis Model.

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: 'CRPS' (78.7% CRPS; 6.5% CLP); 'CLP' (64.5% CLP; 4.9% CRPS), and 'Mixed' (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia (p < 0.001, η² > 0.58). 'CRPS' demonstrated higher psychological and evoked pain measures vs. 'CLP'. 'Mixed' exhibited similarities to 'CRPS' in psychological profile and to 'CLP' in evoked pain measures. The serum level of TNF-αwas higher in the 'CRPS' vs. 'CLP' (p < 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker.

Lessons from applied large-scale pooling of 133,816 SARS-CoV-2 RT-PCR tests.

Pooling multiple swab samples before RNA extraction and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis has been proposed as a strategy to reduce costs and increase throughput of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tests. However, reports on practical large-scale group testing for SARS-CoV-2 have been scant. Key open questions concern reduced sensitivity due to sample dilution, the rate of false positives, the actual efficiency (number of tests saved by pooling), and the impact of infection rate in the population on assay performance. Here, we report an analysis of 133,816 samples collected between April and September 2020 and tested by Dorfman pooling for the presence of SARS-CoV-2. We spared 76% of RNA extraction and RT-PCR tests, despite the frequently changing prevalence (0.5 to 6%). We observed pooling efficiency and sensitivity that exceeded theoretical predictions, which resulted from the nonrandom distribution of positive samples in pools. Overall, our findings support the use of pooling for efficient large-scale SARS-CoV-2 testing.

Personalized Biometrics of Physical Pain Agree with Psychophysics by Participants with Sensory over Responsivity.

The study of pain requires a balance between subjective methods that rely on self-reports and complementary objective biometrics that ascertain physical signals associated with subjective accounts. There are at present no objective scales that enable the personalized assessment of pain, as most work involving electrophysiology rely on summary statistics from a priori theoretical population assumptions. Along these lines, recent work has provided evidence of differences in pain sensations between participants with Sensory Over Responsivity (SOR) and controls. While these analyses are useful to understand pain across groups, there remains a need to quantify individual differences more precisely in a personalized manner. Here we offer new methods to characterize pain using the moment-by-moment standardized fluctuations in EEG brain activity centrally reflecting the person's experiencing temperature-based stimulation at the periphery. This type of gross data is often disregarded as noise, yet here we show its utility to characterize the lingering sensation of discomfort raising to the level of pain, individually, for each participant. We show fundamental differences between the SOR group in relation to controls and provide an objective account of pain congruent with the subjective self-reported data. This offers the potential to build a standardized scale useful to profile pain levels in a personalized manner across the general population.

An Exploratory Study Testing Autonomic Reactivity to Pain in Women with Sensory Over-Responsiveness.

BACKGROUND: Difficulty modulating sensory input related to multi-sensory integration dysfunction, specifically the sensory over-responsive (SOR) type, is associated with psychological distress and hyperalgesia in children and adults. Scares reports suggest atypical autonomic nervous system (ANS) reactivity to innocuous sensory stimuli in children with SOR. Thus, the ANS may contribute to sensory stimuli responses and psychological distress. This exploratory study aimed to characterize the ANS reactivity to single and dual pain stimulation, and in relation to psychological distress in adults with SOR. METHODS: Healthy women with SOR (n = 9) vs. without SOR (n = 9) underwent two runs of single pain stimulation and a third run comprised of dual pain stimulation. Pain was self-rated, while heart rate variability was measured and analyzed in the time and frequency domains. In addition, questionnaires assessing anxiety and somatization were utilized. RESULTS: While controls demonstrated a vagal tone withdrawal (root mean square of successive differences in R-R-intervals; (RMSSD)) p = 0.029 from base-line to the third run, this was absent in the SOR group. However, no group differences were found in pain ratings. Furthermore, groups differed in the correlations between R-R mean and the level of both anxiety (p = 0.006) and somatization (p < 0.001); while in the SOR group, higher levels of anxiety and somatization correlated with shorter R-R intervals, the opposite was found in the control group. CONCLUSIONS: This is the first study to demonstrate in women with SOR atypical vagal tone reactivity to challenging pain load. Vagal tone reactivity is related to both pain ratings and psychological distress.

Structural abnormalities in the temporalis musculo-aponeurotic complex in chronic muscular temporomandibular disorders.

Some forms of chronic pain are thought to be driven and maintained by nociceptive input, which can drive plasticity within nociceptive pathways. We have previously identified abnormalities along the entire nociceptive pathway in chronic myalgic temporomandibular disorders (mTMD), including the trigeminal nerves, brainstem pathways, and in the thalamus and somatosensory cortex. These data suggest that there is a peripheral nociceptive drive in mTMD, but the source of this nociceptive activity remains unknown. Here, our aim was to determine whether structural abnormalities exist in the muscles of mastication of patients with chronic mTMD. Specifically, we tested whether the volume of the temporalis muscle and its tendon-aponeurosis complex (TAC, a structure that dissipates forces in a muscle) in mTMD patients differ compared to age- and sex-matched controls. To do so, we segmented these structures on T1-weighted structural magnetic resonance images. We found that muscle volumes in mTMD were not different to controls. However, the mTMD group had significantly smaller volumes of the bilateral temporalis TAC, and thus a smaller TAC-to-muscle volume ratio. These findings were consistent across 2 independent cohorts of 17 mTMD patients, compared to 17 age- and sex-matched controls. We propose a model where reduced TAC-to-muscle ratio could result in a predisposition to muscle tissue injury. In sum, abnormalities of the temporalis muscles in mTMD supports our hypothesis that chronic mTMD pathophysiology may be related to peripheral nociceptive barrage originating from the muscles of mastication.

A dual-brain approach for understanding the neuralmechanisms that underlie the comforting effects of social touch.

Across different cultures, social touch is used to alleviate distress. Here we adopt a dual-brain approach with fMRI to examine whether social touch involves similar activations between the suffering 'target' and the empathizer in brain regions related to emotional sharing such as the observation-execution (mirror) network. To inspect the neural underpinnings of the effects of social touch on pain, we scanned romantic couples during a task that required one partner (the empathizer) to hold the target's hand as the latter experienced painful thermal stimulation. Empathizers and target participants were scanned sequentially, in two counterbalanced phases. Results revealed that hand-holding reduced the pain of the target participant, compared to the severity of pain in a control condition (holding a rubber ball). Importantly, during social touch we found striking shared activations between the target and empathizer in the inferior parietal lobule (IPL), a region related to the observation-execution network. The brain-to-brain analysis further revealed a positive correlation of IPL activation levels between the target and the empathizer. Finally, psychophysiological interaction (PPI) analysis in the target showed that the IPL activity during social touch was positively coupled with activity in the dorsomedial prefrontal cortex, a region that has been implicated in emotion regulation, suggesting that the interaction between the observation-execution network and emotion regulation network may contribute to pain reduction during social touch.

The Endogenous Analgesia Signature in the Resting Brain of Healthy Adults and Migraineurs.

Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in temporal summation of pain and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with 1) stronger rsFCs of the posterior cingulate cortex, with the ventromedial prefrontal cortex and with the pregenual anterior cingulate cortex; 2) weaker rsFC of the anterior insula with the angular gyrus. Conversely, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. PERSPECTIVE: This article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in health and in the presence of chronic pain.

The "virtual lesion" approach to transcranial magnetic stimulation: studying the brain-behavioral relationships in experimental pain.

Transcranial magnetic stimulation (TMS) can be used to create a temporary "virtual lesion" (VL) of a target cortical area, disrupting its function and associated behavior. Transcranial magnetic stimulation can therefore test the functional role of specific brain areas. This scoping review aims at investigating the current literature of the "online" TMS-evoked VL approach to studying brain-behavioral relationships during experimental pain in healthy subjects. Ovid-Medline, Embase, and Web of Science electronic databases were searched. Included studies tested different TMS-based VLs of various pain brain areas during continuous experimental pain or when time-locked to a noxious stimulus. Outcome measures assessed different pain measurements. Initial screening resulted in a total of 403 studies, of which 17 studies were included in the review. The VLs were directed to the prefrontal, primary and secondary somatosensory, primary motor, and parietal cortices through single/double/triple/sequence of five-TMS pulses or through repeated TMS during mechanical, electrical contact, radiant heat, or capsaicin-evoked noxious stimulation. Despite a wide variability among the VL protocols, outcome measures, and study designs, a behavioral VL effect (decrease or increase in pain responses) was achieved in the majority of the studies. However, such findings on the relationships between the modified brain activity and the manifested pain characteristics were often mixed. To conclude, TMS-elicited VLs during experimental pain empower our understanding of brain-behavior relationships at specific time points during pain processing. The mixed findings of these relationships call for an obligatory standard of all pain-related TMS protocols for clearly determining the magnitude and direction of TMS-induced behavioral effects.

Sensory Modulation Disorder (SMD) and Pain: A New Perspective.

Sensory modulation disorder (SMD) affects sensory processing across single or multiple sensory systems. The sensory over-responsivity (SOR) subtype of SMD is manifested clinically as a condition in which non-painful stimuli are perceived as abnormally irritating, unpleasant, or even painful. Moreover, SOR interferes with participation in daily routines and activities (Dunn, 2007; Bar-Shalita et al., 2008; Chien et al., 2016), co-occurs with daily pain hyper-sensitivity, and reduces quality of life due to bodily pain. Laboratory behavioral studies have confirmed abnormal pain perception, as demonstrated by hyperalgesia and an enhanced lingering painful sensation, in children and adults with SMD. Advanced quantitative sensory testing (QST) has revealed the mechanisms of altered pain processing in SOR whereby despite the existence of normal peripheral sensory processing, there is enhanced facilitation of pain-transmitting pathways along with preserved but delayed inhibitory pain modulation. These findings point to central nervous system (CNS) involvement as the underlying mechanism of pain hypersensitivity in SOR. Based on the mutual central processing of both non-painful and painful sensory stimuli, we suggest shared mechanisms such as cortical hyper-excitation, an excitatory-inhibitory neuronal imbalance, and sensory modulation alterations. This is supported by novel findings indicating that SOR is a risk factor and comorbidity of chronic non-neuropathic pain disorders. This is the first review to summarize current empirical knowledge investigating SMD and pain, a sensory modality not yet part of the official SMD realm. We propose a neurophysiological mechanism-based model for the interrelation between pain and SMD. Embracing the pain domain could significantly contribute to the understanding of this condition's pathogenesis and how it manifests in daily life, as well as suggesting the basis for future potential mechanism-based therapies.